@article{bb2740a4426e4db485360cd30f4432bc,
title = "A variance component-based gene burden test",
abstract = "We propose a novel variance component approach for the analysis of next-generation sequencing data. Our method is based on the detection of the proportion of the trait phenotypic variance that can be explained by the introduction of a new variance component that accounts for the local gene-specific departure of the empirical kinship relationship matrix, estimated from single-nucleotide polymorphism (SNP) genotypes, from their theoretical expectation based on the genealogical information in the pedigree. We tested our method with simulated phenotypes and imputed SNP genotypes from the Genetic Analysis Workshop 18 data set. We observed considerable variation in the differences between theoretical and gene-specific kinship estimates that proved to be informative for our test and allowed us to detect the MAP4 causal gene at a genome-wide significance level. The distribution of our test statistic show no inflation under the null hypothesis and results from a random set of genes suggest that the detection of MAP4 is both sensitive and specific. The use of 2 different strategies for the selection of the SNPs used to derive the gene-specific empirical kinship relationship matrices provides us with suggestive evidence that our method is performing as an empirical test of linkage.",
author = "Peralta, {Juan M.} and Marcio Almeida and Kent, {Jack W.} and John Blangero",
note = "Funding Information: T2D-GENE is supported by NIH grants U01 DK085524, U01 DK085501, U01 DK085526, U01 DK085584, and U01 DK085545. The San Antonio Family Heart Study is supported by P01 HL045222; the San Antonio Family Diabetes Study is supported by R01 DK047482; the San Antonio Family Gallbladder Study is supported by R01 DK053889. SOLAR is supported by National Institute of Mental Health grant MH059490. The supercomputing facilities used for this work at the AT&T Genetics Computing Center were supported in part by a gift from the SBC Foundation. The GAW18 whole genome sequence data were provided by the T2D-GENES Consortium, which is supported by NIH grants U01 DK085524, U01 DK085584, U01 DK085501, U01 DK085526, and U01 DK085545. The other genetic and phenotypic data for GAW18 were provided by the San Antonio Family Heart Study and San Antonio Family Diabetes/Gallbladder Study, which are supported by NIH grants P01 HL045222, R01 DK047482, and R01 DK053889. The Genetic Analysis Workshop is supported by NIH grant R01 GM031575. This article has been published as part of BMC Proceedings Volume 8 Supplement 1, 2014: Genetic Analysis Workshop 18. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcproc/ supplements/8/S1. Publication charges for this supplement were funded by the Texas Biomedical Research Institute. Publisher Copyright: {\textcopyright} 2014 Peralta et al.; licensee BioMed Central Ltd.",
year = "2014",
month = jun,
day = "17",
doi = "10.1186/1753-6561-8-S1-S49",
language = "English (US)",
volume = "8",
journal = "BMC Proceedings",
issn = "1753-6561",
publisher = "BioMed Central",
}